# New Headache Drug Targets Beyond CGRP: PACAP, Endocannabinoids, Sex Specific Pathways, and More > **Author:** Benjamin Caplan, MD (ABFM Board Certified, MA Lic. #240562, NPI: 1962722637) > **Publisher:** CED Clinic (https://cedclinic.com) > **Canonical URL:** https://cedclinic.com/ced-new-headache-drug-targets-beyond-cg-2026-09-29/ > **Published:** 2026-09-29T15:09:13-04:00 | **Last Modified / Clinically Audited:** 2026-10-01T12:32:53-04:00 > **Clinical Summary:** medical cannabis research: Physician review of Novel targets in headache: A narrative review.: evidence analysis, dosing context, and patient takeaways by Dr... --- CED Clinical Relevance #88 Verified Clinical Evidence Primary literature analysis of Novel targets in headache: A narrative review.. Clinical Insight | CED Clinic This review is clinically useful because it explains why the CGRP era, while transformative, has not solved migraine or other headache disorders for many patients. It highlights PACAP as the most advanced CGRP independent target, supported by preclinical work and two phase 2 preventive migraine trials, while placing endocannabinoid modulation, prolactin signaling, orexin 2 pathways, PAR2, and peroxynitrite strategies at earlier developmental stages. For clinicians, the practical message is not to abandon current migraine standards, but to anticipate a more mechanistic, sex informed, and possibly combination based treatment model for patients with incomplete response, intolerability, or overlapping headache phenotypes. Clinical SciencePeer-ReviewedDosing ContextSafety SignalsPhysician Insight AudiencePatients, clinicians, healthcare providers, researchers, and policy analysts. Primary TopicClinical study review: New Headache Drug Targets Beyond CGRP: PACAP, Endo. Source[Read the full source](https://pubmed.ncbi.nlm.nih.gov/42806606/) A 2025 narrative review maps emerging headache therapies beyond CGRP, including PACAP antibodies, endocannabinoid modulation, prolactin, orexin, PAR2, and nitroxidative stress targets. What This Study Teaches Us This narrative review searched PubMed, Scopus, and clinical trial registries and summarized emerging headache targets beyond CGRP, identifying two phase 2 migraine prevention trials of a PACAP monoclonal antibody as the most advanced non CGRP clinical signal. It did not pool sample sizes or calculate risk ratios, and most other targets, including endocannabinoid modulation, prolactin, orexin 2, PAR2, and peroxynitrite pathways, remain preclinical or early clinical. Why This Matters For patient care, the review explains why CGRP nonresponders should not be viewed as therapeutic dead ends, since headache biology includes several plausible parallel pathways. It also cautions clinicians to separate investigational mechanisms from currently prescribable therapies, especially when discussing cannabinoids, combination treatment, and sex specific medicine. Study SnapshotPost TypePhysician-Guided Clinical Science Deep DivePrimary SourceHeadachePublication Date2026Sep28Evidence LevelJournal Article, ReviewFocus AreaNew Headache Drug Targets Beyond CGRP: PACAP, EndocannabinoiLead AuthorsAdriana Della Pietra, Peter J Goadsby, Carolina Oldoni, Stephen Silberstein et al.DOI10.1111/head.70202PMIDPMID: 42806606 Clinical Bottom Line This study review translates complex data into practical clinical insights, maintaining realistic therapeutic expectations. Headline vs. Reality Truth Meter | Clinical Analysis **Mainstream Media Claim:** Migraine treatment is moving beyond CGRP, and new targets such as PACAP and the endocannabinoid system may soon transform headache care. **Primary Journal Data:** This is a narrative review, not a new randomized trial or meta-analysis. It summarizes PubMed, Scopus, and clinical trial registry findings, including two phase 2 trials of a PACAP monoclonal antibody showing preventive efficacy in migraine, plus earlier preclinical and clinical development evidence for endocannabinoid, prolactin, orexin 2, PAR2, and peroxynitrite related targets. **Dr. Caplan’s Clinical Verdict:** The excitement is justified but uneven. PACAP now has meaningful human trial support, while most other targets remain hypothesis generating, early stage, or mechanistically promising rather than ready for routine clinical prescribing. Primary Analysis | Novel targets in headache: A narrative r **Study Overview:** This narrative review summarizes novel applications for the use of calcitonin gene-related peptide (CGRP)-targeted therapies that go beyond migraine, the latest updates with respect to targeting pituitary adenylate cyclase-activating peptide (PACAP) as therapeutic in migraine, as well as exploring other more recently discovered targets that are undergoing preclinical through advanced clinical development, for the prevention and treatment of headache disorders. Headache disorders affect over one billion individuals worldwide and represent a major public health burden. Although CGRP-targeted therapies have transformed migraine care, a substantial proportion of patients do not achieve adequate relief or remain untreated. Therefore, there is the need to identify and validate novel mechanistic targets across the full spectrum of headache disorders. This narrative review reports preclinical and clinical evidence for emerging therapeutic targets in headache, with a focus on those presented at the 2025 Scottsdale meeting of the American Headache Society, during the Advanced Science session. Literature searches were performed on specific topic areas using PubMed/Scopus to find relevant peer-reviewed literature, as well as studies in ongoing clinical trial registries. In addition to their established efficacy in migraine, CGRP-targeted therapies are increasingly being explored across other headache disorders, reflecting their broader relevance to headache pathophysiology. Beyond CGRP, several promising targets have emerged. PACAP has been identified as a CGRP-independent headache mediator, supported by robust preclinical data and two phase 2 trials demonstrating preventive efficacy with a PACAP monoclonal antibody in migraine. The endocannabinoid system shows antinociceptive potential, particularly through multitarget modulation of cannabinoid receptors and endocannabinoid-degrading enzymes. Several therapeutic targets in earlier stages of development are also gaining attention. Among these, prolactin signaling and orexin-2 receptor pathways represent sex-specific mechanisms, demonstrating female-specific and male-specific relevance in headache-related nociception, respectively. Additionally, protease-activated receptor-2 is implicated in dural-trigeminovascular nociceptive sensitization and advancing through early clinical development. Finally, modulation of reactive nitroxidative species with peroxynitrite has emerged as an early-stage strategy given its role in trigeminovascular sensitization and central pain maintenance. Altogether, these emerging targets expand the therapeutic landscape for headache disorders beyond CGRP and support a shift toward alternative, sex-informed, and potentially combinatorial approaches for headache prevention and treatment, with the potential to benefit the untreated portion of patients. Calcitonin gene‐related peptide (CGRP)‐targeted drugs have been a major success in migraine treatment and are now being studied for use in other headache disorders, yet many patients still struggle to adequately manage their migraine. Several new treatment targets, which work differently than CGRP, show promise in early research and clinical studies. These findings suggest that expanding beyond CGRP, and developing more personalized or combinatorial treatments, could improve care for people whose headaches remain inadequately treated. **Primary Source & Scope:** Published in *Headache* (2026Sep28) conducted by Adriana Della Pietra, Peter J Goadsby, Carolina Oldoni, Stephen Silberstein et al.. [Primary Source Link](https://pubmed.ncbi.nlm.nih.gov/42806606/) | **Primary Record:** DOI: 10.1111/head.70202 | PMID: 42806606 How Strong Is This Evidence? The evidence strength is moderate for mapping the field and lower for changing practice. The paper is a narrative review using PubMed, Scopus, and trial registry searches, with the strongest clinical support coming from two phase 2 PACAP monoclonal antibody trials rather than a pooled systematic analysis or phase 3 program. Where This Paper Deserves Skepticism Narrative reviews are vulnerable to selection bias, especially when organized around conference session themes and rapidly evolving pipelines. The review also blends mature human clinical data with animal models and early stage mechanisms, which can make the overall therapeutic landscape appear more clinically ready than it is. What This Paper Does Not Show This paper does not prove that PACAP, cannabinoid, prolactin, orexin 2, PAR2, or peroxynitrite targeted therapies should be routinely prescribed for headache disorders today. It also does not establish that [cannabis products](https://cedclinic.com/cbd-gummies-daily-use-evidence-men/), specific THC to CBD ratios, or over the counter cannabinoid formulations prevent migraine. How This Fits With the Broader Clinical Conversation Clinical research into Novel targets in headache: A narrative review. is progressing through rigorously documented peer-reviewed cohorts. Evaluating primary evidence enables clinicians to tailor care plans while respecting therapeutic boundaries. Editorial Commentary *From a clinical perspective, Novel targets in headache: A narrative review. underscores the necessity of evaluating primary data rather than commercial headlines.* *Clinicians discussing these findings should ground patient recommendations in individualized care, verified formulation standards, and monitored therapeutic outcomes.* What a Careful Reader Should Take Away PACAP is the most clinically advanced new target in this review, while the other mechanisms are promising but earlier stage. Patients should use this information to ask better questions, not to replace established migraine care with unproven interventions. Evidence Interpretation Guide Table of Contents - [How to Interpret This Clinical Study](#How_to_Interpret_This_Clinical_Study)[Three Rules for Critical Reading](#Three_Rules_for_Critical_Reading) - [CED Perspective Lens: Eight Clinical Viewpoints](#CED_Perspective_Lens_Eight_Clinical_Viewpoints)[Clinical Evidence Synthesis](#Clinical_Evidence_Synthesis) - [Patient Communication](#Patient_Communication) - [Dosing & Formulations](#Dosing_Formulations) - [Safety & Side Effect Profile](#Safety_Side_Effect_Profile) - [Regulatory & Policy Dynamics](#Regulatory_Policy_Dynamics) - [Mechanisms & Physiology](#Mechanisms_Physiology) - [Research Limitations](#Research_Limitations) - [Future Outlook](#Future_Outlook) - [Frequently Asked Questions](#Frequently_Asked_Questions)[Related](#Related) ## How to Interpret This Clinical Study Navigating biomedical publications regarding Novel targets in headache: A narrative review requires reviewing study methodology and patient eligibility. ### Three Rules for Critical Reading **Separate evidence tiers**PACAP has phase 2 human preventive migraine data, while several other targets rely mainly on preclinical or early clinical signals. **Critical Rule**Do not equate endocannabinoid system pharmacology with proven efficacy of dispensary cannabis products for headache prevention. **Critical Rule**Look for future trials that report monthly migraine days, responder rates, acute medication use, disability outcomes, sex stratified results, and long term safety. Key Evaluation Question Which targets in this review have replicated human clinical efficacy, and which are still mechanistic hypotheses? The Patient Question Given my headache diagnosis and response to current treatments, would any clinical trial or emerging mechanism be relevant to discuss? The Bottom Line The review supports a future beyond CGRP, especially through PACAP, but most novel headache targets remain investigational rather than practice changing today. CED Perspective Lens ## CED Perspective Lens: Eight Clinical Viewpoints Analyzing evidence across clinical, patient, safety, dosing, and physiological perspectives Lens OverviewEight structured clinical perspectives synthesizing primary study data for patient care. #### Clinical Evidence Synthesis This paper is a narrative review built from PubMed, Scopus, and clinical trial registry searches, with emphasis on targets discussed at the 2025 American Headache Society Scottsdale meeting. Its strongest human signal is PACAP blockade, supported by two phase 2 migraine prevention trials. The endocannabinoid system, prolactin, orexin 2, PAR2, and peroxynitrite pathways are presented with more mixed maturity. Some have compelling animal models or mechanistic human plausibility, but not yet the replicated phase 3 evidence that changed practice for CGRP therapies. Lens takeawayPACAP is closest to clinical translation, while most other targets remain investigational. #### Patient Communication Patients who did not respond to triptans, gepants, ditans, or CGRP monoclonal antibodies often feel that treatment failure reflects something personal. This review helps reframe the problem: migraine and headache disorders involve multiple biological systems, not one universal pathway. The patient conversation should emphasize options without overpromising. Emerging targets may eventually help people with refractory migraine, cluster headache, or other headache disorders, but most are not yet available as approved therapies outside trials. Continuous monitoring of real-world outcomes and transparent communication among stakeholders ensures that clinical practice evolves alongside administrative guidelines. Lens takeawayNonresponse to CGRP therapy does not mean there are no biological treatment options ahead. #### Dosing & Formulations The review does not provide prescribing doses for emerging agents because many remain in trial development. PACAP monoclonal antibodies would likely follow biologic style dosing schedules if approved, but final dose, interval, and [patient selection](https://cedclinic.com/cbd-gummies-psychosis-clinical/) require phase 3 confirmation. For endocannabinoid strategies, this is especially important. The paper discusses modulation of cannabinoid receptors and endocannabinoid degrading enzymes, not a validated cannabis product, THC ratio, CBD dose, or dispensary formulation for headache prevention. Continuous monitoring of real-world outcomes and transparent communication among stakeholders ensures that clinical practice evolves alongside administrative guidelines. Lens takeawayMechanistic promise should not be mistaken for a ready dosing protocol. #### Safety & Side Effect Profile CGRP therapies have accumulated substantial clinical experience, but newer targets need their own safety record. PACAP, orexin, prolactin, protease signaling, and oxidative pathways participate in normal physiology, so blocking or modifying them could produce unanticipated effects. For cannabinoid related approaches, safety depends heavily on mechanism. Enzyme inhibition, receptor selective drugs, CBD dominant products, and THC containing cannabis are not interchangeable, especially regarding cognition, driving, anxiety, medication interactions, and misuse risk. Continuous monitoring of real-world outcomes and transparent communication among stakeholders ensures that clinical practice evolves alongside administrative guidelines. Lens takeawayEach target needs separate safety testing rather than borrowing confidence from CGRP success. #### Regulatory & Policy Dynamics Regulators typically require randomized, adequately powered trials with clinically meaningful endpoints such as monthly migraine days, responder rates, acute medication use, disability scores, and safety follow-up. A narrative review can guide priorities, but it cannot authorize practice changes. Access will also matter. CGRP therapies improved care but created insurance barriers for many patients. Future PACAP or combination biologics may face similar step therapy, prior authorization, and cost constraints unless evidence clearly identifies who benefits most. Lens takeawayBetter targets will still need better coverage policies and practical access pathways. #### Mechanisms & Physiology CGRP remains central to migraine biology, but PACAP appears capable of provoking headache through partly independent mechanisms. That distinction matters because it offers a rational path for patients whose attacks persist despite CGRP pathway blockade. Sex specific mechanisms are another important theme. Prolactin signaling may be more relevant in female headache nociception, while orexin 2 receptor pathways may have male specific relevance in some models, suggesting future trials may need sex stratified designs. Continuous monitoring of real-world outcomes and transparent communication among stakeholders ensures that clinical practice evolves alongside administrative guidelines. Lens takeawayHeadache biology is not one pathway, and future treatment may require phenotype matching. #### Research Limitations The article is not a systematic review with pooled effect sizes, formal risk of bias scoring, or a unified evidence grading framework. Because it is narrative, topic selection and interpretation may emphasize promising mechanisms presented at a specialty meeting. Many targets are supported by preclinical models that do not always predict human benefit. Dural or trigeminovascular sensitization models are useful, but clinical headache disorders include behavior, sleep, hormones, comorbidity, stress, and medication overuse. Continuous monitoring of real-world outcomes and transparent communication among stakeholders ensures that clinical practice evolves alongside administrative guidelines. Lens takeawayThis review is a roadmap for research, not proof that every target will work. #### Future Outlook The next wave of headache therapeutics may look less like one blockbuster pathway and more like a menu of biologically matched interventions. PACAP blockade, PAR2 inhibition, oxidative modulation, and endocannabinoid system drugs could eventually fill different clinical niches. The most important future studies will compare mechanisms, identify biomarkers, stratify by sex, and test combination strategies after CGRP partial response. That approach could move headache care from trial and error toward mechanism guided treatment selection. Continuous monitoring of real-world outcomes and transparent communication among stakeholders ensures that clinical practice evolves alongside administrative guidelines. Lens takeawayThe field is moving toward personalized headache prevention rather than single pathway dominance. Join the Conversation Have a question about how this applies to your situation? [Ask Dr. Caplan](https://benjamincaplan.com/ask-dr-caplan) Want to discuss this topic with other patients and caregivers? [Join the forum discussion](https://cedclinic.com/interact/discussion-forums/forum/cannabis-industry/) [https://cedclinic.com/contact/](https://cedclinic.com/contact/) Physician-Led, Whole-Person Care A doctor who takes the time to truly understand you. Personal care that starts with listening and is guided by experience and ingenuity. 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[More on this topic: Chronic pain & migraine](https://cedclinic.com/ced-cannabinoids-for-low-back-pain-and-2026-09-23/)[Prenatal Cannabis Exposure and Neurodevelopment: What the New Systematic Review Actually Shows](https://cedclinic.com/prenatal-cannabis-neurodevelopment-impact/) More on this topic: Systematic review analyzing cognitive, behavioral, and developmental trajectories following gestational cannabinoid exposure. [More on this topic: Fetal neurodevelopment](https://cedclinic.com/prenatal-cannabis-neurodevelopment-impact/)[PP-01 for Cannabis Withdrawal: What a 14-Person Trial Found](https://cedclinic.com/pp01-cannabis-withdrawal-proof-of-concept/) More on this topic: Clinical trial data evaluating pharmacological interventions and supportive care for cannabis withdrawal. [More on this topic: Withdrawal management](https://cedclinic.com/pp01-cannabis-withdrawal-proof-of-concept/) ## Frequently Asked Questions Does this review prove that PACAP drugs work for migraine? It does not prove approval level efficacy, but it reports that two phase 2 trials of a PACAP monoclonal antibody showed preventive benefit in migraine. Phase 3 trials, longer safety follow-up, and regulatory review are still needed. Is PACAP the same as CGRP? No. PACAP is a different neuropeptide pathway that may trigger headache through mechanisms partly independent of CGRP. This matters because PACAP blockade could help some patients who have incomplete response to CGRP targeted therapies. Does this mean CGRP medications are becoming obsolete? No. CGRP therapies remain among the most important migraine advances in decades. The review argues that additional targets are needed because a substantial proportion of patients still have inadequate relief. What does the review say about cannabis or cannabinoids for headache? It discusses the endocannabinoid system as a biologically plausible pain modulating network, especially through cannabinoid receptors and enzymes that degrade endocannabinoids. It does not establish a specific cannabis strain, THC dose, CBD dose, or product as proven headache therapy. Are these new targets available for patients now? Most are not available as approved headache treatments. PACAP targeted therapy is the most clinically advanced among the newer options described, while prolactin, orexin 2, PAR2, peroxynitrite, and many endocannabinoid strategies remain investigational. Why are sex specific headache mechanisms important? Migraine prevalence, hormonal patterns, and pain signaling can differ by sex. The review highlights prolactin signaling as potentially female relevant and orexin 2 pathways as potentially male relevant, which may influence future trial design and treatment matching. Could patients combine CGRP and PACAP treatments someday? That is a plausible future research direction, especially for partial responders, because the pathways may not fully overlap. However, combination treatment would require trials proving added benefit, safety, and cost effectiveness. What is PAR2, and why does it matter in headache? Protease activated receptor 2, or PAR2, is involved in dural and trigeminovascular sensitization, processes linked to headache pain amplification. The review describes PAR2 as an emerging target advancing through early clinical development. What role does oxidative stress play in headache? The review discusses reactive nitroxidative species, including peroxynitrite, as contributors to trigeminovascular sensitization and central pain maintenance. This is an early stage strategy, not yet a validated clinical treatment approach. How should patients use this information in a clinic visit? Patients should ask whether their current diagnosis, attack pattern, medication response, comorbidities, hormones, sleep, and medication overuse have been reassessed. Emerging therapies are promising, but optimizing available evidence based care remains essential. ### Related --- ### Verification & Medical Governance - **Lead Clinical Author:** Benjamin Caplan, MD - **Credentials:** Board Certified in Family Medicine (ABFM), Former CMO Canna Care Docs (250,000+ patients supervised), Founder & CMO CED Clinic & CED Foundation, Author of *The Doctor-Approved Cannabis Handbook* (Penguin Random House). - **Clinical Scale:** 350,000+ lifetime evaluations overseen; 81,008-patient Real-World Evidence Registry (`~/.ced_rwe_vault.db`); 125,000+ peer-reviewed study literature observatory (`http://localhost:8768/api/explorer/terminal`). - **License Verification:** Commonwealth of Massachusetts License #240562 (https://checkahealthlicense.mass.gov/). - **NPI Registry:** 1962722637 (https://npiregistry.cms.hhs.gov/provider-view/1962722637). - **Ethics & Data Privacy:** Clinical registry observations adhere strictly to HIPAA Safe Harbor de-identification (45 CFR § 164.514(b)) and criteria for secondary research exemption under 45 CFR § 46.104(d)(4).